Cyclic amides of aminocarboxylic acids are called lactams; β-lactams have four rings. β-lactams are extremely important as the basic backbones of β-lactam antibiotics such as penicillin, cephalosporin and the like, and the synthesis of these compounds has long been widely studied.
Judging from the structure of β-lactams, synthesis by the cyclization of β-amino acids would appear to be most appropriate. If it were possible to cyclize β-amino acids directly by heating, this would be easy; however, it is known that β-amino acids themselves undergo 1,2- dissociation when heated, and do not form β-lactams (Shin-Jikken Kagaku Koza, Yuki Kagobutsu no Gosei to Hanno [Synthesis and reaction of organic compounds](2), Maruzen, p. 1197, (1978)). Methods in which β-amino acids are acylated and then subjected to direct heating cyclization (J. C. Sheehan and E. J. Corey, Org. React., 9, 393 (1957)), methods in which amino acid chlorides are treated with bases (F. F. Blicke and W. A. Gould, J. Org. Chem., 23, 1102 (1958)), methods in which β-amino acid esters are cyclized with a Grignard reagent (T. Kametani et. al., Tetrahedron, 37, 715 (1981)) and the like have long been reported. Meanwhile, in regard to methods for the cyclization of β-amino acids themselves, methods using ring-closing agents such as phosphorus trichloride, carbodiimide and the like have been studied. For example, β-lactams have been obtained by reacting free β-amino acids in acetonitrile using dichlorophosphoric acid and triethylamine (C. W. Kim and B. Y. Chung, Tetrahedron Lett., 31, 2905 (1990)). This method suffers from the following drawbacks: namely, highly toxic reagents and harmful organic solvents are used, and these compounds must be disposed of; furthermore, the reaction process is complicated and the reaction time is long. However, almost no method for the direct, simple and efficient cyclization of β-amino acids is known, and the development of such a method is currently awaited.
Under such conditions, the present inventors pursued various studies concerning methods for synthesizing β-lactams under high temperature and high pressure in light of the abovementioned prior art. In the process of this research, the inventors have discovered that β-lactams can be manufactured with good efficiency by reacting β-amino acids in water at high-temperature and under high-pressure conditions. Further research was conducted on the basis of this finding, and this research led to the perfection of the present invention.